rs12575909

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024740.2(ALG9):c.1604T>G(p.Ile535Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,924 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 35 hom. )

Consequence

ALG9
NM_024740.2 missense, splice_region

Scores

Splicing: ADA: 0.3635

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.78

Variant links:

Genes affected

ALG9 (HGNC:15672): (ALG9 alpha-1,2-mannosyltransferase) This gene encodes an alpha-1,2-mannosyltransferase enzyme that functions in lipid-linked oligosaccharide assembly. Mutations in this gene result in congenital disorder of glycosylation type Il. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ALG9 links:

ENSG00000258529 (HGNC:):

ENSG00000258529 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064125657).

BP6

Variant 11-111809772-A-C is Benign according to our data. Variant chr11-111809772-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 235406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-111809772-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00151 (230/152294) while in subpopulation EAS AF= 0.043 (223/5186). AF 95% confidence interval is 0.0384. There are 6 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG9	NM_024740.2 linkuse as main transcript	c.1604T>G	p.Ile535Ser	missense_variant, splice_region_variant	14/15	ENST00000616540.5	NP_079016.2	Q9H6U8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG9	ENST00000616540.5 linkuse as main transcript	c.1604T>G	p.Ile535Ser	missense_variant, splice_region_variant	14/15	1	NM_024740.2	ENSP00000482437.1		Q9H6U8-3
ENSG00000258529	ENST00000622211.4 linkuse as main transcript	c.2282T>G	p.Ile761Ser	missense_variant, splice_region_variant	18/19	2		ENSP00000482396.1		A0A087WZ62

Frequencies

GnomAD3 genomes

AF:

0.00151

AC:

230

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0429

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00311

AC:

775

AN:

249402

Hom.:

AF XY:

0.00286

AC XY:

387

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0423

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.00110

AC:

1605

AN:

1461630

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

754

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0374

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00147

GnomAD4 genome

AF:

0.00151

AC:

230

AN:

152294

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0430

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.00176

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00302

AC:

365

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 02, 2015

- -

ALG9 congenital disorder of glycosylation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D;D;D

MetaRNN

Benign

0.0064

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.6

L;.;.;.;.

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.7

.;D;D;.;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0060

.;D;D;.;.

Sift4G

Uncertain

0.015

D;D;D;D;D

Polyphen

0.0080

B;.;.;B;.

Vest4

0.67

MVP

0.97

MPC

0.49

ClinPred

0.14

GERP RS

5.7

Varity_R

0.21

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.36

dbscSNV1_RF

Benign

0.46

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over